Decoding PRC2 stage-specific roles during germline-embryo-germline transition

Early mammalian development undergoes a series of precisely regulated processes, including the maternal-to-zygotic transition (MZT), the first lineage specifications, gastrulation, and the primordial germ cell (PGC) specification. While key transcription factors (TFs) and epigenetic modifiers that regulate these events have been investigated, the intricate transcriptional and epigenetic networks, such as interplays between TFs and chromatin modifications remain to be fully established. The Polycomb Repressive Complex 2 (PRC2) mediates transcriptional silencing by depositing H3K27me3 and is essential for proper gastrulation. However, the PRC2 function in early development may not be fully captured due to limitations of conventional knockout approaches. Here we applied the degradation tag (dTAG) system to deplete the PRC2 acutely and stage-specifically in mouse pre- and early post-implantation development. This work revealed previously underappreciated functions of PRC2 in regulating key events in early development including the MZT, the first and second cell lineage specifications. In addition, we demonstrated that PRC2 restricts premature activation of developmental genes in embryonic day (E)4.5 inner cell mass (ICM) cells, facilitating proper epiblast specification. Moreover, systematic analysis of H3K27me3 and H3K4me3 dynamics reveals that epigenetics interplay drives the chromatin bivalency establishment at E4.5 ICM, which is earlier than previously thought that the bivalency appears at post-implantation stages. Lastly, we elucidated the lineage crosstalk dependent PRC2-ESRRB-BMP4 signal axis in regulating PGCs specification during gastrulation. Together, our results demonstrate that PRC2 plays stage-specific roles through dual interplay with epigenetic modification and transcription factors during germline-embryo-germline transition.